ABSTRACT Relationships between viruses and DNA damage response (DDR) in host are well described and show that viruses modulate cell metabolism and interact with cellular mechanisms to activate or deactivate different pathways in DNA damage repair. Cells with affected DNA repair pathway were shown to be more vulnerable to targeting DDR causing increases in DNA damage to the level that trigger apoptosis. There is growing evidence that HIV-1 influence DDR during active infection, however, nothing is known about DDR in HIV-1 reservoirs, where virus remains latent. We showed for the first time that latently infected cells exhibit deficiencies in DDR, indicating that HIV-1 latency have influence on host ability to efficiently respond to DNA damage. We also found that latent cells are more susceptible to the agent inducing double strand breaks (DSBs). Moreover, exposing latently infected cells to agents targeting telomeres caused increases in the rate of apoptosis. Thus, we propose to investigate a hypothesis that latently infected cells have an impaired DDR, and that this deficiency can be efficiently targeted to cure HIV. In Aim 1, we will determine the susceptibility of the latently infected central memory T-cells to DNA damage-inducing agents. Whereas, in Aim 2, we will investigate the role of specific DDR proteins and viral proteins in sensitizing latently infected memory T-cells to DNA damage. These aims will be undertaken by a strong multidisciplinary team of investigators who has proven expertise in HIV latency, biochemistry and cell biology, and a history of productive collaboration to successfully complete these investigations. Moreover, proposed studies will leverage research infrastructure offered by the University of Rochester Center for AIDS Research (UR-CFAR). Our proposal is innovative because it investigates the sensitivity of latently infected cells to DNA damage-inducing agents, which will break new ground explaining previously unrecognized functional consequences of latency in both health and disease. This study is significant because revealing the DDR mechanisms affected by HIV will provide a critical basic science foundation to understand how these molecular pathways function in latently infected cells, while providing insight into how targeting them could eliminate HIV reservoirs without viral reactivation. The results obtained in these studies are expected to exert a high impact on HIV/AIDS field on three counts: 1) by advancing scientific knowledge and revealing how HIV impairs DDR in memory T-cells, which will propel further investigations into the mechanisms that can be exploited for effective cure, 2) by promoting novel methodologies, and 3) by validating disease-modifying therapeutic targets, which are also viable in other viral infections.